Pharmaceutical compositions of valdecoxib

ABSTRACT

The present invention relates to novel crystalline forms of valdecoxib, to processes for their preparation and to pharmaceutical compositions containing them.

FIELD OF THE INVENTION

The present invention relates to novel crystalline forms of valdecoxib,to processes for their preparation and to pharmaceutical compositionscontaining them.

BACKGROUND OF THE INVENTION Valdecoxib of Formula (I)

or 4-(5-Methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide is a highlyselective and potent cyclooxygenase-2 inhibitor in human whole blood anduseful for the treatment of arthritis and pain. The therapeutic uses ofvaldecoxib are disclosed in WO 9625405.

Two crystalline forms of valdecoxib, form A and form B, are mentioned inWO 9806708.

We have discovered three stable novel crystalline forms of valdecoxiband these forms are found to be suitable for pharmaceuticalpreparations.

The object of the present invention is to provide stable novelcrystalline forms of valdecoxib, processes for preparing these forms andpharmaceutical compositions containing them.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a novelcrystalline form of valdecoxib, designated as form 1, characterized byan x-ray powder diffraction pattern having peaks expressed as 2θ atabout 9.7, 13.1, 14.0, 14.5, 17.0, 17.1, 17.7, 19.4, 20.9, 21.3, 21.8,24.1, 25.4, 26.3 and 29.1 degrees. FIG. 1 shows typical form I x-raypowder diffraction pattern.

In accordance with the present invention, a process is provided forpreparation of valdecoxib form I. In this process, valdecoxib isdissolved in dimethyl formamide or N,N-dimethyl acetamide and valdecoxibform I is isolated from the solution. Valdecoxib in any crystalline formmay be used. If valdecoxib form I is used in the process, its serves asa method of purification of valdecoxib form I. A mixture of dimethylformamide and N,N-dimethyl acetamide; or dimethyl formamide orN,N-dimethyl acetamide mixed with any other solvent may be used.Valdecoxib form I can be isolated by the techniques like cooling,partial removal of the solvent or combination thereof. Crystallizationmay be initiated with the aid of seed crystals. Preferably, valdecoxibis mixed with dimethyl formamide or N,N-dimethyl acetamide and heated toabout 50° C. to reflux temperature. The solution so formed is preferablymaintained at 25° C. to 30° C. for 3 to 5 hours and the valdecoxib formI crystals formed are separated by filtration or centrifugation.

In accordance with the present invention, there is provided a novelcrystalline form of valdecoxib, designated as form II, characterized byan x-ray powder diffraction pattern having peaks expressed as 2θ atabout 12.2, 15.4, 15.9, 19.9, 20.6, 22.0, 23.0, 23.6, 23.9, 24.5, 25.1,28.6 and 31.3 degrees. FIG. 2 shows typical form II x-ray powderdiffraction pattern.

In accordance with the present invention, a process is provided forpreparation of valdecoxib form II. In this process, valdecoxib isdissolved in acetonitrile and isolated valdecoxib form II from thesolution. Valdecoxib in any crystalline form may be used. Preferablyvaldecoxib is dissolved in acetonitrile at about 40° C. to 45° C. andvaldecoxib form II is separated at about 25° C.-30° C. The valdecoxibform II may be collected by filtration or centrifugation.

In accordance with the present invention, there is provided a novelcrystalline form of valdecoxib, designated as form III, characterized byan x-ray powder diffraction pattern having peaks expressed as 2θ atabout 11.6, 12.2, 12.9, 13.3, 15.4, 15.7, 16.7, 17.0, 17.4, 18.1, 19.7,20.6, 21.9, 22.4, 23.1, 23.4, 23.8, 24.4, 25.3, 25.7, 26.1, 28.5 and29.7 degrees. FIG. 3 shows typical form III x-ray powder diffractionpattern.

In accordance with the present invention, a process is provided forpreparation of valdecoxib form III. In this process, valdecoxib isdissolved in an ester solvent and isolated valdecoxib form III from thesolution. Preferably the solution is cooled to 5° C. to 30° C. to getthe crystals of valdecoxib form III. The valdecoxib form III may becollected by filtration or centrifugation. Valdecoxib in any crystallineform may be used in the process. The suitable ester solvent is selectedfrom n-butyl acetate, ethyl acetate, methyl acetate, isopropyl acetate,tert-butyl acetate, ethyl formate, methyl formate. A combination of theester solvents may also be used.

In accordance with the present invention, there is provided apharmaceutical composition comprising form I of valdecoxib and apharmaceutically acceptable carrier or diluent.

In accordance with the present invention, there is provided apharmaceutical composition comprising form II of valdecoxib and apharmaceutically acceptable carrier or diluent.

In accordance with the present invention, there is provided apharmaceutical composition comprising form III of valdecoxib and apharmaceutically acceptable carrier or diluent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a x-ray powder diffraction spectrum of valdecoxib form I.

FIG. 2 is a x-ray powder diffraction spectrum of valdecoxib form II.

FIG. 3 is a x-ray powder diffraction spectrum of valdecoxib form III.

x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-raypowder diffractometer having a copper-Kα radiation.

The following examples are given for the purpose of illustrating thepresent invention and should not be considered as limitations on thescope of spirit of the invention.

Example 1

Valdecoxib (10 gm, obtained by the process described in example 1 of WO9625405) is dissolved in dimethyl formamide (50 ml), heated to 50° C.and the solution obtained is cooled to 25° C. and maintained at 25° C.to 30° C. for 3 hours. The separated crystals are filtered to give 9 gmof valdecoxib form I.

Example 2

Valdecoxib (10 gm) is dissolved in acetonitrile (125 ml), heated to 40°C. and the solution obtained is cooled to 25° C. and maintained at 25°C. to 30° C. for 6 hours. The separated crystals are filtered to give9.5 gm of valdecoxib form II.

Example 3

Example 1 is repeated using valdecoxib form II for valdecoxib to givevaldecoxib form I.

Example 4

Example 2 is repeated using valdecoxib form I for valdecoxib to givevaldecoxib form II.

Example 5

Valdecoxib (10 gm) is mixed with n-butyl acetate (100 ml), heated to 80°C. The solution so formed is cooled to 25° C. and maintained at about25° C. for 5 hours. The separated crystals are filtered to give 8.5 gmof valdecoxib form III.

Example 6

Example 5 is repeated using valdecoxib form II for valdecoxib to givevaldecoxib form III.

1-14. (canceled)
 15. A pharmaceutical composition comprising stablevaldecoxib form I characterized by an x-ray powder diffraction patternhaving peaks expressed as 2θ at about 9.7, 13.1, 14.0, 14.5, 17.0, 17.1,17.7, 19.4, 20.9, 21.3, 21.8, 24.1, 25.4, 26.3 and 29.1 degrees and apharmaceutically acceptable carrier or diluent. 16-17. (canceled) 18.The pharmaceutical composition of claim 15, wherein the valdecoxib formI is further characterized by an x-ray powder diffraction pattern as inFIG.
 1. 19. The pharmaceutical composition of claim 15, wherein thevaldecoxib form I is prepared by a process which comprises the steps of:(a) dissolving valdecoxib in dimethyl formamide or N,N-dimethylacetamide; and (b) isolating valdecoxib form I from the solution. 20.The pharmaceutical composition of claim 19, wherein valdecoxib isdissolved in dimethyl formamide.
 21. The pharmaceutical composition ofclaim 19, wherein the solution formed in (a) is cooled to 25° C. to 30°C. and the separated crystals are collected by filtration orcentrifugation.